Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes

Abstract

Significance: Nicotinamide adenine dinucleotide (NAD⁺) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD⁺ depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD⁺, and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD⁺ levels. Recent studies have shown that enhancing NAD⁺ levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD⁺ anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the de novo NAD⁺ synthesis pathway in mammalian cells. NAD⁺ can also be produced by the NAD⁺ salvage pathway. Recent Advances: In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD⁺ precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD⁺ decline in degenerative disease states and physiological aging. Critical Issues: Results obtained in recent years have shown that NAD⁺ precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD⁺ synthesis via their location in the NAD⁺ anabolic pathway. Increased synthesis of NAD⁺ promotes protective cell responses, further demonstrating that NAD⁺ is a regulatory molecule associated with several biochemical pathways. Future Directions: In the next few years, the refinement of personalized therapy for the use of NAD⁺ precursors and improved detection methodologies allowing the administration of specific NAD⁺ precursors in the context of patients' NAD⁺ levels will lead to a better understanding of the therapeutic role of NAD⁺ precursors in human diseases.

Keywords: DNA damage; NAD; nicotinamide; oxidative stress; sirtuins.

FIG. 1.

Putative relationship between changes in tryptophan catabolism and de novo NAD⁺ synthesis in ADC neuropathology. Immune-activated oxidative l-tryptophan catabolism can contribute positively to the maintenance of cell viability through increased metabolism of NAD⁺ in astrocytes and mononuclear phagocytes. However, chronic activation of this pathway may also enhance neuronal excitotoxicity through the production of QUIN and possibly 3-HK. 3-HK, 3-hydroxykynurenine; ADC, AIDS dementia complex; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-gamma; NAD⁺, nicotinamide adenine dinucleotide; PARP, poly(ADP-ribose) polymerase; QUIN, quinolinic acid. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

The NAD⁺ metabolome. l-TRYP, NA, NAM, NMN, NR, and NAR can be used as precursors for NAD⁺ synthesis. (A) l-TRYP is catabolized to N-formylkynurenine (N-f-KYN) by IDO or TDO. (B) N-f-KYN is catabolized by arylformidase to form KYN. (C) KATs catabolize KYN to form KA. (D) Kynurenine 3-hydroxylase uses KYN as a substrate to form 3-HK. (E) Kynureninase then forms 3-HAA, which is converted to 2-amino-3-carboxymuconate semialdehyde (not shown) by (F) 3-HAAO. (G) This product is then converted to picolinic acid by picolinic acid carboxylase. (H) Alternatively, the semialdehyde undergoes spontaneous condensation and rearrangement to form QUIN, which forms NAMN by (I) QPRT. (U) NAMN undergoes adenylylation by NMNAT1-3 to form NAAD, which forms NAD⁺ by (M) glutamine-dependent NAD⁺ synthetases. NA is used by the Preiss–Handler pathway. (L) NAMN is formed by NAPRT following addition of 5-phosphoribose group from PRPP to NA. (P) NAMPT forms NMN by addition of phosphoribose moiety to NAM. (U) NMN is then converted to NAD⁺ via the catalytic activity of NMNAT1-3. (N) NAM is also produced as a by-product of NAD-dependent enzymes, for example, PARPs, sirtuins, and CD38. (O) NAM can also be converted to NA by bacterial nicotinamidases. (J) NR is phosphorylated to form NMN by NRK1/NRK2, which is then subsequently converted to NAD⁺ by NMNAT1-3. (J) NAR can also be used to form NAMN by NRK1/NRK2 or (K) NA by purine nucleoside phosphorylase. (Q) NAM is methylated NNMT to MeNAM and modulates the efficiency of NAD-dependent biological processes. (T) NAD⁺ can be reduced to form NADH. (R) NAD⁺ can also undergo phosphorylation to NADP⁺ (S) and then further reduction to NADPH. 3-HAA, 3-hydroxyanthranilic acid; 3-HAAO, 3-hydroxyanthranilic acid oxygenase; KA, kynurenic acid; KATs, kynurenine aminotransferases; KYN, kynurenine; l-TRYP, l-tryptophan; MeNAM, N-methylnicotinamide; NA, nicotinic acid; NAAD, nicotinic acid adenine dinucleotide; NAM, nicotinamide; NAMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinic acid phosphoribosyltransferase; NAR, nicotinic acid riboside; NMN, nicotinamide mononucleotide; NMNAT, nicotinamide mononucleotide adenylyltransferase; NNMT, nicotinamide N-methyltransferase; NR, nicotinamide riboside; NRK, nicotinamide riboside kinase; PRPP, 5-phosphoribosyl-1-pyrophosphate; QPRT, quinolinic acid phosphoribosyltransferase; TDO, tryptophan 2,3-dioxygenase.

FIG. 3.

Concomitant induction of IDO and free radical generation by IFN-γ. Chronic immune activation of macrophages and astrocytes will result in increased reactive oxygen and nitrogen species and elevates glutamate levels (in the absence of efficient uptake into astrocytes). A possible relationship exists between IFN-γ-stimulated free radical production and IDO induction, leading to increased de novo synthesis of NAD⁺. IFN-γ, interferon-gamma. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Cofactors required for QPRT activity and NAD⁺ synthesis. PRPP is important for the regulation of QPRT activity. PIC, picolinic acid. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Cellular roles of NAD⁺. The mechanisms of degradation of NAD⁺, including CD38, PARPs, and sirtuins. NAD⁺ can be phosphorylated to NADP⁺. There are also oxireduction reactions of NAD⁺ to NADH and NADP⁺ to NADH. CD38 is an NAD-dependent enzyme that leads to the production of cADPR from NAD⁺ and NADP⁺, respectively. Cytosolic cADPR target to ryanodine receptors on endoplasmic reticulum, and transient receptor potential mucolipin 1 on lysosomes, regulating intracellular calcium signaling from the endoplasmic reticulum and lysosome-mediated intracellular calcium signaling. cADPR, cyclic-ADP-ribose. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Modulation of PARP activity. (A) PARP and PARG enzymatic activity. PARP breaks down NAD⁺ to NAM and an ADP-ribosyl product degradation of ADP-ribose polymers occurs relatively rapidly through the action of PARG. (B) Relationship between DNA damage, PARP activation, and NAD⁺ depletion. Under normal physiological conditions, PARP activation leads to repair of damaged DNA. However, increased PARP activity resulting in decreased NAD⁺ has been shown to decrease ATP as well as cause cell lysis and death (45, 203) (B). PARG, poly(ADP-ribose) glycohydrolase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 7.

Stoichiometry of CD38-mediated Ca²⁺ mobilizing and NADase activities. (A) CD38 requires NAD⁺ to produce ADPR and hydrolyze the secondary messenger signaling molecule, cADPR, which helps mediate intracellular calcium transients. ADPR, ADP ribose. (B) CD38 also converts NADP⁺ to NAADP⁺ via base exchange (NADase activity of CD38). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 8.

Schematic representation of CD38-mediated intracellular Ca²⁺ secondary messenger signaling. CD38 is also an NADase, which primarily regulates intracellular levels of NAD⁺ and its physiological processes. CD38 also catalyzes a base exchange between NADP and NA, leading to the formation of NAADP, which is also used as a hydrolytic substrate. NAADP, nicotinic acid adenine dinucleotide phosphate. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 9.

Sirtuin enzymatic activity. NAM is rendered as a by-product of sirtuin-mediated deactylation. Deacetylation occurs when the modified lysine side chain is coupled to the cleavage of the glycosidic bonds in NAD⁺, leading to the generation of the deacetylated lysine, acetylated ADP-ribose, and NAM as by-products. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 10.

Functions of NAD-dependent sirtuins and relevant transcription factors. Sirtuin-mediated deacetylation affects numerous target enzymes and transcription factors relevant to aging and disease. Importantly, sirtuin activities stimulate OXPHOS, while yet unknown acetylation mechanisms serve to inhibit anti-OXPHOS. OXPHOS, oxidative phosphorylation. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 11.

Modulation of NAD⁺ and NAD-dependent pathways by caloric restriction in mice and humans. Caloric restriction has been shown to increase neuronal SIRT1 activity in humans. In mice, hepatic total NAD⁺ levels increased in fasted mice, and these changes were accompanied by increased SIRT1 activation, PGC1α deacetylation, and increased mitochondrial biogenesis. SIRT, sirtuin. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 12.

Chemical structure of NAD⁺ precursors.

FIG. 13.

Mechanisms of action of NA in dyslipidemia. The lipid-lowering effects of NA are thought to be mediated by binding of NA to the cell surface of a G-protein-coupled receptor known as HM74A or GPR109A. This association in adipocytes suppresses triglyceride lipolysis, culminating in the reduction of circulating fatty acids, and reduced liver very LDL formation and circulating LDL-cholesterol. LDL, low-density lipoprotein. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 14.

Schematic representation of the molecular mechanism of skin flushing following treatment with NA. NA-mediated stimulation of HM74A in some skin immune cells results in the conversion of the omega-6 metabolite AA into prostaglandin E2, stimulating vasodilation of skin capillaries, causing skin flush. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 15.

Mechanisms of action of NAM and its effect on the NAD⁺ metabolome. NAM also serves as a natural feedback inhibitor for NAD-dependent enzymes. For example, PARP, sirtuin, and CD38 activities are proportionately inhibited as NAM concentrations increase, and this has been postulated as the mechanism for the antidiabetic effects of NAM in humans. While NAD⁺ levels are still elevated, the important NAD-dependent functions (e.g., SIRT1 activity) are inhibited. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars